Specific targeting is common in biology and is a key challenge in nanomedicine. It was recently demonstrated that multivalent probes can selectively target surfaces with a defined density of surface binding sites. Here we show, using a combination of experiments and simulations on multivalent polymers, that such "superselective" binding can be tuned through the design of the multivalent probe, to target a desired density of binding sites. We develop an analytical model that provides simple yet quantitative predictions to tune the polymer's superselective binding properties by its molecular characteristics such as size, valency, and affinity. This work opens up a route toward the rational design of multivalent probes with defined superselective targeting properties for practical applications, and provides mechanistic insight into the regulation of multivalent interactions in biology. To illustrate this, we show how the superselective targeting of the extracellular matrix polysaccharide hyaluronan to its main cell surface receptor CD44 is controlled by the affinity of individual CD44-hyaluronan interactions.tunability | superselectivity | host-guest multivalent interactions | hyaluronan

Despite their importance for material and life sciences, multivalent interactions between polymers and surfaces remain poorly understood. Combining recent achievements of synthetic chemistry and surface characterization, we have developed a well-defined and highly specific model system based on host/guest interactions. We use this model to study the binding of hyaluronic acid functionalized with host molecules to tunable surfaces displaying different densities of guest molecules. Remarkably, we find that the surface density of bound polymer increases faster than linearly with the surface density of binding sites. Based on predictions from a simple analytical model, we propose that this superselective behavior arises from a combination of enthalpic and entropic effects upon binding of nanoobjects to surfaces, accentuated by the ability of polymer chains to interpenetrate.

Double-stranded DNA (dsDNA) can trigger the production of type I interferon (IFN) in plasmacytoid dendritic cells (pDCs) by binding to endosomal Toll-like receptor-9 (TLR9; refs 1-5). It is also known that the formation of DNA-antimicrobial peptide complexes can lead to autoimmune diseases via amplification of pDC activation. Here, by combining X-ray scattering, computer simulations, microscopy and measurements of pDC IFN production, we demonstrate that a broad range of antimicrobial peptides and other cationic molecules cause similar effects, and elucidate the criteria for amplification. TLR9 activation depends on both the inter-DNA spacing and the multiplicity of parallel DNA ligands in the self-assembled liquid-crystalline complex. Complexes with a grill-like arrangement of DNA at the optimum spacing can interlock with multiple TLR9 like a zipper, leading to multivalent electrostatic interactions that drastically amplify binding and thereby the immune response. Our results suggest that TLR9 activation and thus TLR9-mediated immune responses can be modulated deterministically.

properties of living matter (cells, tissues) are very sensitive to temperature, while those of 'formerly living' matter (say, a piece of wood) are not. Multivalent interactions: Why so sensitive ?Imagine two multivalent entities at a fixed distance that are connected by a number of bonds (say k). The two entities can dissociate only when all k bonds are broken. We denote the probability that an individual bond is broken by p unbound 1 and the probability that all k bonds are broken by p unbound k . If different bonds do not influence each other, the probability of unbinding isNote that for large 'valencies' k, the relation between p unbound 1 and p unbound k is highly non-linear. In fact, the expression for the ratio between probabilities p unbound k /p bound k can be written in a form reminiscent of the Hill equation:where the exponent k plays a role similar to that of the Hill coefficient (Eq. (3.1)).The probability of a single bond spontaneously breaking p unbound 1 will depend not only on control parameters such as bond strength, temperature, pH of the solution etc., but also on the number of possible bonding arrangements. Clearly, the unbinding probability, Eq. (3.2), tends to be very sensitive to any parameter that influences p unbound 1 . This example illustrates the physical origins of ultrasensitive response in multivalent interactions. We shall see below that competition between different bonds modifies the response but retains ultra-sensitivity.In what follows, we focus on the ultra-sensitivity of multivalent interactions to the density of 'receptors' on the substrate surface. In particular, we will derive expressions that show how the binding strength of a multivalent entity (say a liganddecorated nanoparticle or a multivalent polymer) to a substrate changes with the concentration of receptors 2) on the substrate surface (see Figure 3.2). It will turn out that multivalent interactions can be designed such that they result in an almost step-like switch from unbound to bound as the receptor concentration exceeds a well-defined threshold value. In the remainder of this chapter, we will use the term 'super selectivity' to denote this kind of sharp response.2) A brief comment on the use of terminology: we make liberal use of the terms 'ligand' and 'receptor' with which we shall denote individual binding partners. 'Receptors' will be found on the substrate surface whilst individual 'ligands' are attached to the multivalent entity (say, a nano-particle) that binds to the substrate, shown in Figures 3.2 and 3.3. We use the term 'multivalent entity' to denote any moiety that is able to form multiple bonds. The term 'binding site' always denotes an individual monovalent interaction site, equivalent to a single 'ligand' or 'receptor'.

This is a repository copy of Multivalent recognition at fluid surfaces: the interplay of receptor clustering and superselectivity.